The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Cancer is a devastating disease afflicting all communities worldwide. It has been estimated that 1 out of 2 men and 1 out 3 women will develop some form cancer within their lifetime. It is also estimated that more than 550,000 people will die due to cancer in the United States alone during 2005. Cancer is a generalized term for a complex and vastly different set of diseases related to the uncontrolled growth, survival, and invasion of cells. Although there are more than 100 different types of cancer, as well as subtypes of each, recent studies have revealed limited number of genetic elements which are required for transformation of benign cells to cancer cells (Zhao et al., 2004). Generally, it has been concluded that human cell transformation requires activation of Ras GTPase, overexpression of telomerase, inactivation of tumor suppressor proteins p53 and Retinoblastoma protein (Rb) and inhibition of protein phosphatase 2A (PP2A) (Zhao et al., 2004). It is obvious that understanding of the function of these genetic elements could lead to development of cancer therapies that would be widely applicable to different types of cancer.
As described above, inhibition of PP2A activity has been identified as one of the prerequisites for transformation of primary human cells (Zhao et al., 2004). PP2A is a trimeric protein complex consisting of a catalytic subunit (PP2Ac or C), a scaffold subunit (PR65 or A) and one of the alternative regulatory B subunits (FIG. 1A)(Janssens and Goris, 2001). PP2A regulates cellular behaviour by dephosphorylating regulatory ser/thr residues of the protein kinases and other signaling proteins. Oncogenic transcription factor c-Myc is one of the many substrates for PP2A. It was recently shown, that PP2A-mediated dephosphorylation of serine 62 on c-Myc results in proteosomal degradation of the protein (Yeh et al., 2004). Importantly, viral small t-antigen, which inactivates PP2A, exerts its oncogenic potential by stabilization of c-Myc (Yeh et al., 2004).
Even though the importance of PP2A inhibition for human cell transformation has been firmly established by using viral antigens as research tools, the molecular mechanisms by which PP2A inhibition occurs in spontaneously transformed human cancer cells is currently not understood. There is thus an identified need of elucidating the mechanism by which PP2A inhibits transformation.